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Evaluating the Safety and Efficacy of Anti-Influenza Intravenous Hyperimmune Immunoglobulin (IVIG) in Adults Hospitalized With Influenza

Primary Purpose

Influenza A, Influenza B

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Intravenous hyperimmune immunoglobulin (IVIG)
Placebo for IVIG
Sponsored by
National Institute of Allergy and Infectious Diseases (NIAID)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Influenza A focused on measuring Antiviral, IVIG, Hemagglutination inhibition (HAI), Antibody

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Signed informed consent
  • Locally determined positive influenza test (by polymerase chain reaction [PCR] or other nucleic acid test, or by rapid antigen [Ag]) from a specimen obtained within 2 days prior to randomization
  • Onset of illness no more than 7 days before randomization, defined as when the participant first experienced at least one respiratory symptom or fever
  • Hospitalized (or in observation unit) for influenza, with anticipated hospitalization for more than 24 hours. Criteria for hospitalization will be up to the individual treating clinician.
  • For women of child-bearing potential: willingness to abstain from sexual intercourse or use at least one form of hormonal or barrier contraception through Day 28 of the study
  • Willingness to have blood and respiratory samples obtained and stored
  • NEW score greater than or equal to 2 at screening (see the protocol for more information on this criterion)

Exclusion Criteria:

  • Women who are pregnant or breast-feeding
  • Strong clinical evidence (in the judgment of the site investigator) that the etiology of illness is primarily bacterial in origin
  • Prior treatment with any investigational drug therapy within 30 days prior to screening
  • History of allergic reaction to blood or plasma products (as judged by the site investigator)
  • Known immunoglobulin A (IgA) deficiency
  • A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the participant at a substantially increased risk of thrombosis (e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically significant monoclonal gammopathy)
  • Presence of any pre-existing illness that, in the opinion of the site investigator, would place the participant at an unreasonably increased risk through participation in this study
  • Participants who, in the judgment of the site investigator, will be unlikely to comply with the requirements of this protocol
  • Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be dangerous to the participant (e.g., decompensated congestive heart failure)
  • Receiving extracorporeal membrane oxygenation (ECMO)
  • Suspicion that infection is due to an influenza strain or subtype other than A(H1N1)pdm09, H3N2, or influenza B (e.g., H5N1, H7N9)

Sites / Locations

  • UCSD Antiviral Research Center (A VRC)
  • Denver Public Health
  • University of Illinois
  • National Institutes of Health Clinical Center
  • Henry Ford Hospital
  • Minneapolis VA Medical Center
  • Mayo Clinic
  • Cooper University Hospital
  • Montefiore Medical Center
  • Cornell CRS
  • Duke University
  • Case Western Reserve University
  • OHIO State University (OSU) Wexner Medical Center
  • Miami Valley Hospital
  • University of Pittsburgh
  • UT Southwestern Medical Center
  • West Virginia University
  • Westmead Hospital
  • Odense University Hospital
  • St James's University Hospital
  • Churchill Hospital

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Arm A: hIVIG

Arm B: Placebo

Arm Description

Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu.

Participants will receive a single infusion of placebo for hIVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu.

Outcomes

Primary Outcome Measures

Number of Patients in Each of 6 Clinical Status Categories on Day 7
This is the primary outcome, a 6-category ordinal outcome ranging from death (worst) to discharged from hospital with resumption of normal activities (best).

Secondary Outcome Measures

Number of Patients in Each of 5 Clinical Status Categories on Day 3
5-category ordinal outcome assessed on day 3; clinical status ranges from death (worst) to discharged from the hospital (best).
Number of Patients in Each of 6 Clinical Status Categories on Day 3
6-category ordinal outcome evaluated on Day 3; clinical status ranges from death (worst) to discharged from hospital with resumption of normal activities (best).
Number of Patients With a Favorable Outcome on Day 7
Sliding dichotomy defined as non-ICU hospitalization or discharge if enrolled from ICU, and discharge if enrolled from the general ward.
Hospital Discharge
Number of participants alive and discharged from the hospital
Mortality
Number of participants dying through day 28.
Number of Patients Alive and Out of Hospital
Number and percent alive and out of hospital on day 28
Change in Viral Load
Change in nasopharyngeal viral load from baseline to day 3
Death or Re-hospitalization
Number and percent of participants who died or were re-hospitalized after initial discharge
Percent of Participants Developing Complications
Number and percent of participants developing respiratory distress syndrome, acute renal failure, sepsis, pneumonia, enteritis, or bronchitis
Number of Patients in Each of 6 Clinical Status Categories on Day 14
6-category ordinal outcome measured on day 14
Number of Patients Alive and Out of Hospital on Day 14
Number and percentage of participants alive and out of the hospital on Day 14
Resumption of Normal Activities by Day 14
Participants reporting resumption of normal daily activities by Day 14
Number of Patients in Each of 6 Clinical Status Categories on Day 28
6-category ordinal outcome corresponding to clinical status on day 28
Number of Influenza A-Infected Patients in Each of 6 Clinical Status Categories on Day 7
Primary 6-category ordinal outcome for participants infected with Influenza A
Number of Influenza B-Infected Patients in Each of 6 Clinical Status Categories on Day 7
Primary 6-category ordinal outcome for subgroup of participants infected with influenza B
pH1N1 Titers at Day 7
pH1N1 hemagglutination inhibition assay (HAI) titers among participants infected with pH1N1 using A/Cal/2009 as reference virus
H3N2 Titers at Day 7
H3N2 HAI titers among participants infected with H3N2 using A/HongKong/2014 as reference virus
Influenza B Titers at Day 7
Flu B HAI titers among participants infected with influenza B using B/Phuket/2013 as reference virus

Full Information

First Posted
November 6, 2014
Last Updated
November 11, 2019
Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
University of Minnesota, International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)
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1. Study Identification

Unique Protocol Identification Number
NCT02287467
Brief Title
Evaluating the Safety and Efficacy of Anti-Influenza Intravenous Hyperimmune Immunoglobulin (IVIG) in Adults Hospitalized With Influenza
Official Title
Anti-Influenza Hyperimmune Intravenous Immunoglobulin Clinical Outcome Study (INSIGHT 006: FLU-IVIG)
Study Type
Interventional

2. Study Status

Record Verification Date
November 2019
Overall Recruitment Status
Completed
Study Start Date
January 2015 (undefined)
Primary Completion Date
June 7, 2018 (Actual)
Study Completion Date
June 7, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Institute of Allergy and Infectious Diseases (NIAID)
Collaborators
University of Minnesota, International Network for Strategic Initiatives in Global HIV Trials (INSIGHT)

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Influenza (the flu) is a common illness that usually occurs in autumn and winter. The flu is usually mild, but can cause serious illness or death. The purpose of this study is to test the safety and effectiveness of an antibody against the flu (called intravenous hyperimmune immunoglobulin or IVIG) in people who are hospitalized for severe flu.
Detailed Description
Influenza is responsible for thousands of hospitalizations and deaths each year in the United States and worldwide. One possible new treatment for the flu involves the use of IVIG, a blood product containing antibodies from people who have recovered from the flu or who have had a flu shot. The purpose of this study is to evaluate whether IVIG can reduce the severity and duration of flu in people who are hospitalized with the flu. The study will enroll participants 18 years and older who are hospitalized with the flu. The study will enroll participants over one or more flu seasons. Regardless of the date of enrollment, each participant will be in the study for about 28 days. At study entry (Day 0), participants will be randomly assigned to one of two groups (Arms A and B). Participants in both groups will receive standard of care (SOC) treatment for the flu, but those in Arm A will also receive one dose of IVIG and those in Arm B will receive a placebo for IVIG. Both IVIG and placebo will be given intravenously over at least 2 hours. On Day 0, before receiving IVIG or placebo, participants will undergo a symptoms assessment, blood collection, and a nasopharyngeal (NP) swab to collect a sample of secretions from the nose and throat. Additional study visits will occur on Days 1, 2, 3, 7, 14, and 28. Depending on the visit, participants may take part in the same study procedures that took place on Day 0. On Days 2, 14, and 28, visits for participants who are no longer hospitalized may be conducted over the phone.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Influenza A, Influenza B
Keywords
Antiviral, IVIG, Hemagglutination inhibition (HAI), Antibody

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Allocation
Randomized
Enrollment
329 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Arm A: hIVIG
Arm Type
Experimental
Arm Description
Participants will receive a single infusion of intravenous hyperimmune immunoglobulin (hIVIG), administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu.
Arm Title
Arm B: Placebo
Arm Type
Placebo Comparator
Arm Description
Participants will receive a single infusion of placebo for hIVIG, administered over approximately 2 hours on Day 0. Participants will also receive SOC treatment for the flu.
Intervention Type
Biological
Intervention Name(s)
Intravenous hyperimmune immunoglobulin (IVIG)
Intervention Description
Administered intravenously (IV) at a dose of 0.25 g/kg (up to a maximum of 24.75 g, corresponding to approximately 100 kg actual body weight)
Intervention Type
Biological
Intervention Name(s)
Placebo for IVIG
Intervention Description
Administered IV as 500 mL of normal saline
Primary Outcome Measure Information:
Title
Number of Patients in Each of 6 Clinical Status Categories on Day 7
Description
This is the primary outcome, a 6-category ordinal outcome ranging from death (worst) to discharged from hospital with resumption of normal activities (best).
Time Frame
Assessed on Day 7
Secondary Outcome Measure Information:
Title
Number of Patients in Each of 5 Clinical Status Categories on Day 3
Description
5-category ordinal outcome assessed on day 3; clinical status ranges from death (worst) to discharged from the hospital (best).
Time Frame
Assessed on Day 3
Title
Number of Patients in Each of 6 Clinical Status Categories on Day 3
Description
6-category ordinal outcome evaluated on Day 3; clinical status ranges from death (worst) to discharged from hospital with resumption of normal activities (best).
Time Frame
Measured on Day 3
Title
Number of Patients With a Favorable Outcome on Day 7
Description
Sliding dichotomy defined as non-ICU hospitalization or discharge if enrolled from ICU, and discharge if enrolled from the general ward.
Time Frame
Assessed on Day 7
Title
Hospital Discharge
Description
Number of participants alive and discharged from the hospital
Time Frame
Measured through Day 7
Title
Mortality
Description
Number of participants dying through day 28.
Time Frame
Measured through day 28
Title
Number of Patients Alive and Out of Hospital
Description
Number and percent alive and out of hospital on day 28
Time Frame
Measured through Day 28
Title
Change in Viral Load
Description
Change in nasopharyngeal viral load from baseline to day 3
Time Frame
Day 3
Title
Death or Re-hospitalization
Description
Number and percent of participants who died or were re-hospitalized after initial discharge
Time Frame
Day 28
Title
Percent of Participants Developing Complications
Description
Number and percent of participants developing respiratory distress syndrome, acute renal failure, sepsis, pneumonia, enteritis, or bronchitis
Time Frame
Measured through Day 28
Title
Number of Patients in Each of 6 Clinical Status Categories on Day 14
Description
6-category ordinal outcome measured on day 14
Time Frame
Measured on day 14
Title
Number of Patients Alive and Out of Hospital on Day 14
Description
Number and percentage of participants alive and out of the hospital on Day 14
Time Frame
day 14
Title
Resumption of Normal Activities by Day 14
Description
Participants reporting resumption of normal daily activities by Day 14
Time Frame
day 14
Title
Number of Patients in Each of 6 Clinical Status Categories on Day 28
Description
6-category ordinal outcome corresponding to clinical status on day 28
Time Frame
day 28
Title
Number of Influenza A-Infected Patients in Each of 6 Clinical Status Categories on Day 7
Description
Primary 6-category ordinal outcome for participants infected with Influenza A
Time Frame
Day 7
Title
Number of Influenza B-Infected Patients in Each of 6 Clinical Status Categories on Day 7
Description
Primary 6-category ordinal outcome for subgroup of participants infected with influenza B
Time Frame
Day 7
Title
pH1N1 Titers at Day 7
Description
pH1N1 hemagglutination inhibition assay (HAI) titers among participants infected with pH1N1 using A/Cal/2009 as reference virus
Time Frame
Day 7
Title
H3N2 Titers at Day 7
Description
H3N2 HAI titers among participants infected with H3N2 using A/HongKong/2014 as reference virus
Time Frame
Day 7
Title
Influenza B Titers at Day 7
Description
Flu B HAI titers among participants infected with influenza B using B/Phuket/2013 as reference virus
Time Frame
Day 7

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Signed informed consent Locally determined positive influenza test (by polymerase chain reaction [PCR] or other nucleic acid test, or by rapid antigen [Ag]) from a specimen obtained within 2 days prior to randomization Onset of illness no more than 7 days before randomization, defined as when the participant first experienced at least one respiratory symptom or fever Hospitalized (or in observation unit) for influenza, with anticipated hospitalization for more than 24 hours. Criteria for hospitalization will be up to the individual treating clinician. For women of child-bearing potential: willingness to abstain from sexual intercourse or use at least one form of hormonal or barrier contraception through Day 28 of the study Willingness to have blood and respiratory samples obtained and stored NEW score greater than or equal to 2 at screening (see the protocol for more information on this criterion) Exclusion Criteria: Women who are pregnant or breast-feeding Strong clinical evidence (in the judgment of the site investigator) that the etiology of illness is primarily bacterial in origin Prior treatment with any investigational drug therapy within 30 days prior to screening History of allergic reaction to blood or plasma products (as judged by the site investigator) Known immunoglobulin A (IgA) deficiency A pre-existing condition or use of a medication that, in the opinion of the site investigator, may place the participant at a substantially increased risk of thrombosis (e.g., cryoglobulinemia, severe refractory hypertriglyceridemia, or clinically significant monoclonal gammopathy) Presence of any pre-existing illness that, in the opinion of the site investigator, would place the participant at an unreasonably increased risk through participation in this study Participants who, in the judgment of the site investigator, will be unlikely to comply with the requirements of this protocol Medical conditions for which receipt of a 500 mL volume of intravenous fluid may be dangerous to the participant (e.g., decompensated congestive heart failure) Receiving extracorporeal membrane oxygenation (ECMO) Suspicion that infection is due to an influenza strain or subtype other than A(H1N1)pdm09, H3N2, or influenza B (e.g., H5N1, H7N9)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard T. Davey, Jr., MD
Organizational Affiliation
National Institute of Allergy and Infectious Diseases (NIAID)
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Eduardo Fernández-Cruz, MD, PhD
Organizational Affiliation
Hospital General Universitario Gregorio Marañón
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Norman P. Markowitz, MD
Organizational Affiliation
The Henry Ford Hospital
Official's Role
Study Chair
First Name & Middle Initial & Last Name & Degree
Sarah L. Pett, MD, MBBS, DTM, MRCP (UK)
Organizational Affiliation
University College, London
Official's Role
Study Chair
Facility Information:
Facility Name
UCSD Antiviral Research Center (A VRC)
City
San Diego
State/Province
California
ZIP/Postal Code
92103
Country
United States
Facility Name
Denver Public Health
City
Denver
State/Province
Colorado
ZIP/Postal Code
80204
Country
United States
Facility Name
University of Illinois
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60612
Country
United States
Facility Name
National Institutes of Health Clinical Center
City
Bethesda
State/Province
Maryland
ZIP/Postal Code
20892
Country
United States
Facility Name
Henry Ford Hospital
City
Detroit
State/Province
Michigan
ZIP/Postal Code
48202
Country
United States
Facility Name
Minneapolis VA Medical Center
City
Minneapolis
State/Province
Minnesota
ZIP/Postal Code
55417
Country
United States
Facility Name
Mayo Clinic
City
Rochester
State/Province
Minnesota
ZIP/Postal Code
55905
Country
United States
Facility Name
Cooper University Hospital
City
Camden
State/Province
New Jersey
ZIP/Postal Code
08103
Country
United States
Facility Name
Montefiore Medical Center
City
Bronx
State/Province
New York
ZIP/Postal Code
10467
Country
United States
Facility Name
Cornell CRS
City
New York
State/Province
New York
ZIP/Postal Code
10010
Country
United States
Facility Name
Duke University
City
Durham
State/Province
North Carolina
ZIP/Postal Code
27710
Country
United States
Facility Name
Case Western Reserve University
City
Cleveland
State/Province
Ohio
ZIP/Postal Code
44106
Country
United States
Facility Name
OHIO State University (OSU) Wexner Medical Center
City
Columbus
State/Province
Ohio
ZIP/Postal Code
43210
Country
United States
Facility Name
Miami Valley Hospital
City
Dayton
State/Province
Ohio
ZIP/Postal Code
45409
Country
United States
Facility Name
University of Pittsburgh
City
Pittsburgh
State/Province
Pennsylvania
ZIP/Postal Code
15213
Country
United States
Facility Name
UT Southwestern Medical Center
City
Dallas
State/Province
Texas
ZIP/Postal Code
75235
Country
United States
Facility Name
West Virginia University
City
Morgantown
State/Province
West Virginia
ZIP/Postal Code
26506
Country
United States
Facility Name
Westmead Hospital
City
Sydney
Country
Australia
Facility Name
Odense University Hospital
City
Odense
Country
Denmark
Facility Name
St James's University Hospital
City
Leeds
Country
United Kingdom
Facility Name
Churchill Hospital
City
Oxford
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
31582358
Citation
Davey RT Jr, Fernandez-Cruz E, Markowitz N, Pett S, Babiker AG, Wentworth D, Khurana S, Engen N, Gordin F, Jain MK, Kan V, Polizzotto MN, Riska P, Ruxrungtham K, Temesgen Z, Lundgren J, Beigel JH, Lane HC, Neaton JD; INSIGHT FLU-IVIG Study Group. Anti-influenza hyperimmune intravenous immunoglobulin for adults with influenza A or B infection (FLU-IVIG): a double-blind, randomised, placebo-controlled trial. Lancet Respir Med. 2019 Nov;7(11):951-963. doi: 10.1016/S2213-2600(19)30253-X. Epub 2019 Sep 30.
Results Reference
derived

Learn more about this trial

Evaluating the Safety and Efficacy of Anti-Influenza Intravenous Hyperimmune Immunoglobulin (IVIG) in Adults Hospitalized With Influenza

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